@article{790d69ea97a44f70a72adabb8da8359b,
title = "Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4",
abstract = "The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.",
keywords = "ATF-4, CP: Metabolism, CP: Molecular biology, Zidovudine, aging, geroprotector, lifespan, nucleoside reverse transcriptase inhibitor, translation",
author = "McIntyre, {Rebecca L} and Marte Molenaars and Schomakers, {Bauke V} and Gao, {Arwen W} and Rashmi Kamble and Aldo Jongejan and {van Weeghel}, Michel and {van Kuilenburg}, {Andr{\'e} B P} and Richard Possemato and Houtkooper, {Riekelt H} and Janssens, {Georges E}",
note = "Funding Information: We thank Perry D. Moerland for assistance in analysis of the RNA sequencing. We thank the Caenorhabditis Genetics Center (CGC) at the University of Minnesota for providing C. elegans strains. The CGC is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). M.M. is supported by an EMBO Postdoctoral Fellowship (ALTF 1104-2021) and an HFSP Long-Term Fellowship (881965). G.E.J. is supported by a VENI grant from ZonMw, Talent Development and Innovation grants from the AGEM institute, and support from the Longevity Impetus Grant from Norn Group. R.L.M. R.H.H. and G.E.J. conceived and designed the project. R.L.M. M.M. B.V.S. A.W.G. and R.K. performed experiments. R.L.M. M.M. B.V.S. M.v.W. and G.E.J. analyzed the data. B.V.S. and M.v.W. performed, analyzed, and aided in interpretation of metabolomics data. A.J. and G.E.J. performed bioinformatics analyses of the RNA sequencing data. R.P. aided in interpretation of data and provided advice. R.L.M. G.E.J. and R.H.H. wrote the manuscript with contributions from all other authors. The authors declare no competing interests. Funding Information: We thank Perry D. Moerland for assistance in analysis of the RNA sequencing. We thank the Caenorhabditis Genetics Center (CGC) at the University of Minnesota for providing C. elegans strains. The CGC is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). M.M. is supported by an EMBO Postdoctoral Fellowship ( ALTF 1104-2021 ) and an HFSP Long-Term Fellowship ( 881965 ). G.E.J. is supported by a VENI grant from ZonMw , Talent Development and Innovation grants from the AGEM institute, and support from the Longevity Impetus Grant from Norn Group . Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2023",
month = jan,
day = "31",
doi = "https://doi.org/10.1016/j.celrep.2022.111928",
language = "English",
volume = "42",
pages = "1",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}